The tripeptide Glycyl-L-Prolyl-L-Glutamate (Gly-Pro-Glu or GPE) is a naturally occurring peptide, which is proteolytically cleaved from insulin-like growth factor-1 (IGF-1). IGF-1 is a potent neurotrophic factor produced endogenously in damaged regions of the brain. It has been postulated that some of the neuroprotective actions of IGF-1 are mediated by GPE although the precise mechanism of action remains unclear. GPE has a different mode of action to IGF-1 as GPE does not bind to the IGF-1 receptor. Rather, GPE has been shown to bind with low affinity to the N-methyl-D-aspartate (NMDA) receptor and also elicit a biological response via other mechanisms. GPE facilitates the release of dopamine through interaction with the NMDA receptor but GPE stimulated acetylcholine release is via an unknown, non-NMDA pathway.
It has been demonstrated that GPE can act as a neuronal rescue agent following brain injury or disease, including hypoxic-ischemic brain injury, NMDA challenge, chemical toxins and in animal models of Parkinson's and Alzheimer's disease. Analogs of GPE are thus of interest in the development of novel pharmaceutical agents for the treatment of central nervous system (CNS) injuries and neurodegenerative disorders among others.
The inventors have previously disclosed certain GPE analogs modified at the glycine and/or glutamate residues in order to investigate structure-activity relationships and in an attempt to improve properties such as metabolic stability and oral bioavailability. Some of these are described in U.S. Pat. No. 7,041,314; PCT International Patent Application No: PCT/US02/16361 filed 24 May 2002; U.S. application Ser. No. 11/314,424 filed 20 Dec. 2005; U.S. application Ser. No. 11/315,784 filed 21 Dec. 2005; U.S. patent application Ser. No. 11/398,032 filed 4 Apr. 2006 and U.S. Provisional Patent Application No. 60/782,148 filed 14 Mar. 2006. Each of the aforementioned patents and patent applications is incorporated herein fully by reference. Additionally, certain analogs are described in Trotter et al. Bioorg. Med. Chem. 2005, 13, 501; Lai et al. Bioorg. Med. Chem. 2005, 13, 533; Brimble et al. Bioorg. Med. Chem. 2005, 13, 519).
However, there is an ongoing need for other GPE analogs and compositions for treatment of disorders of the nervous system, including disorders involving neurodegeneration and neural cell death, as well as agents for treating other types of disorders.